The objective of this research program is to define the molecular mechanisms that regulate the functional and phenotypic properties of monocytes. Previous studies have elucidated several proinflammatory activities of TGF-beta including chemotaxis and cytokine induction in monocytes. Prolonged exposure to TGF-beta enhances the responsiveness of monocytes to other inflammatory stimuli including interferon (IFN gamma), interleukin-1 (IL-1), and lipopolysaccharide (LPS). Pretreatment with TGF-beta for 6-48 hr and IL-6, within 30 min after exposure to LPS as compared to untreated cells. In contrast, simultaneous exposure to TGF-beta and another activation signal suppresses the cytokine response. These activation process in monocytes, with TGF-beta providing the initial cytokine. The interaction between these primed cells and inflammatory mediators may contribute to chronic inflammation. Although a variety of cytokines have been identified in inflamed tissue, another compound, nitric oxide, may also play a role in the inflammatory process, providing another type of signal to mediate monocyte function, in this case, microbicidal activity. Preliminary studies have identified increased levels of nitric oxide as measured by nitrite (7 to 30 microM) in synovial cell and tissue culture fluids as well as synovial fluids from rheumatoid arthritis patients. These studies provide evidence for the existence of inducible nitric oxide biosynthesis in human inflammatory disease. Ongoing studies are addressing the possible therapeutic intervention of nitric oxide synthase activity.